The goal of this proposal is to answer a number of fundamental questions regarding the structural basis for the recognition of peptide/MHC class I complexes by T cell receptors (TCRs). Are there general structural principles which govern TCR-MHC interactions? Are these similar for TCR recognition of self and foreign MHC? Does conformational change or induced fit play a role in TCR-MHC recognition and communication among members of the TCR/MHC/CD3/CD8 signalling complex? X-ray crystallography will be used to investigate the detailed molecular interactions between a TCR specific for different syngeneic and allogeneic peptide/MHC class I complexes in the presence and absence of CD3 and CD8 components. The specific aims are to determine the structures of: (i) TCR-MHC syngeneic class I-peptide complexes, (ii) TCR-allogeneic class I-peptide complexes, (iii) TCR/MHC/CD8 ternary complexes, (iv) agonist and antagonist TCR-MHC complexes, and (v) extracellular CD3 chains and their complexes with TCR.